Mukaiyama s protocol

Scheme 2.24 Regioselective formation of boron enolates according to Mukaiyama s protocols transition-state model 91 for kinetically controlled enolate generation.

Mukaiyama s protocol was successfully applied to the synthesis of other P-glycopyranosides and a or P furanosides. 

The key step in the synthesis of A-ring fragment 50 [56] is the chelation-controlled addition of allylstannane 53 to aldehyde 52, which sets the C7 stereocenter and introduces the C8 gem-dimethyl moiety. Aldehyde 52 is itself prepared from 1,3-propanediol using the author s protocol for titanium-catalyzed enantioselective allylstannation [57], which sets the C5 stereocenter, followed by chelation-controlled Mukaiyama aldol addition [58] to establish the C3 stereocenter (Scheme 5.6). 

As an aside, an exhaustive screening of virtually every major lactonization protocol was attempted in this step, but none worked as well as the indicated conditions. Equally important, even with the given protocol the use of MeCN was critical for a high yield of 1 since both Mukaiyama s reagent and the triol carboxylic acid (65) are poorly soluble in neat CH2CI2. 

The most versatile and the most frequently applied among the enantioselective catalytic aldol protocols is based upon the Mukaiyama s directed aldol reaction the addition of silicon enolates to aldehydes or ketones [86], in its classic version under activation of the carbonyl group by a chiral Lewis acid. More recently, base-promoted versions of the Mukaiyama reaction were elaborated and also procedures that involve a transmetallation of the silicon enolate. Over the years since the discovery of the reaction, numerous protocols for enantioselective and diastereoselective additions of silicon enolates to aldehydes or ketones under activation by chiral catalysts were elaborated [87], after the group of Mukaiyama itself had made seminal and substantial contributions [88]. 

The reaction was intensively studied for a-benzyloxyacetaldehyde 219a. When catalyzed by the PYBOX complex 217, various silyl ketene (O and S) acetals 220 give acetate aldol adducts 221 in high chemical yields and enantioselectiv-ity, as shown in Scheme 5.67. Compared with many protocols for asymmetric Mukaiyama reactions, the low catalyst loading (as little as 0.5 mol%) is remarkable. PYBOX catalysis is also an efficient tool for vinylogous Mukaiyama aldol additions, as illustrated also in Scheme 5.67 for acetoacetate-derived silicon enolate... 

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